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A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses

Abstract

Interleukin 17 (IL-17)–producing T helper 17 cells (TH-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (TH1) and TH2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human TH-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-β, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1β and IL-6) were all essential for human TH-17 differentiation. However, individual TH-17 cell–derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global TH-17 cytokine profile, were differentially modulated by TH-17-promoting cytokines. Transforming growth factor-β was critical, and its absence induced a shift from a TH-17 profile to a TH1-like profile. Our results shed new light on the regulation of human TH-17 differentiation and provide a framework for the global analysis of T helper responses.

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Figure 1: TGF-β, IL-23 and proinflammatory cytokines are required for the differentiation of human CD4+ TH-17 cells.
Figure 2: TGF-β, IL-23 and proinflammatory cytokines induce typical TH-17 features.
Figure 3: The TH-17 cytokine profile has specific features but also features that overlap with those of other T helper cell–polarizing conditions.
Figure 4: TH-17 cell–derived cytokines are differentially regulated by TH-17-promoting cytokines.
Figure 5: IL-23 and proinflammatory cytokines induce a TH1-like profile that 'converts' to a TH-17 profile after the addition of TGF-β.

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Acknowledgements

We thank O. Lantz, S. Denépoux, F. Barrat, C. Théry, P. Benaroch, I. Fernandez, Z. Maciorowsky and H. Kitamura for suggestions and critical reading of the manuscript; and Z. Maciorowsky, C. Guérin and A. Viguier for cell sorting. Yssel's medium was a gift from H. Yssel (Institut National de la Santé et de la Recherche Médicale). Supported by the European Community Sixth Framework Programme (Marie Curie Excellence Grant 014162).

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E.V. did experiments and drafted the manuscript; N.S. did computational and statistical analysis; R.Z. did quantitative RT-PCR analysis and helped with the computational data analysis; S.I.B. did some experiments; P.H. did computational and statistical analysis; E.B. supervised the computational and statistical analysis; and V.S. designed and supervised the study and wrote the manuscript.

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Correspondence to Vassili Soumelis.

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Volpe, E., Servant, N., Zollinger, R. et al. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nat Immunol 9, 650–657 (2008). https://doi.org/10.1038/ni.1613

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